“…This phenomenon was similar to the B. subtilis cells treated with 64 µg/mL berberine (Figure S2). These results are also consistent with the reported FtsZ inhibitors, such as benzamide and pyrimidine derivatives,13,29,30 and suggest that CZ74 may disrupt FtsZ function and lead to the abnormal cell division. Figure 2Cell division inhibitory effect of CZ74.…”
Background
The prevalence of drug-resistant bacterial infections urges the development of new antibacterial agents that possess a mechanism of action different from traditional antibiotics. FtsZ has been recognized as a key functional protein in bacterial cell division and it is currently believed to be a potential target for the development of novel antibacterial agents.
Purpose
The primary aim of the study is to screen out an inhibitor targeting at FtsZ and followed to investigate its antibacterial activity and mode of action.
Methods
Cell-based cell division inhibitory screening assay, antimicrobial susceptibility test, minimum bactericidal concentration assay, time-killing curve determination, FtsZ polymerization assay, GTPase activity assay, and molecular modeling were performed in the present study.
Results
The screening study from a small library consisting of benzimidazole and indole derivatives discovered a compound (CZ74) with an indole-core structure. The compound exhibited strong cell division inhibitory effect. In addition, CZ74 shows high antibacterial potency against a number of tested Gram-positive bacteria, such as methicillin-resistant
Staphylococcus aureus
and vancomycin-resistant
Enterococcus
. The minimum inhibitory concentration values obtained were within the range of 2–4 µg/mL. The results of biological study revealed that CZ74 at 2 µg/mL is able to disrupt FtsZ polymerization and inhibit GTPase activity and cell division. From molecular modeling study, CZ74 is found possibly binding into the interdomain cleft of FtsZ protein and then leads to inhibitory effects.
Conclusion
This indole-cored molecule CZ74 could be a potential lead compound and could be further developed as a new generation of antibacterial agents targeting FtsZ to combat against multidrug-resistant bacteria.
“…This phenomenon was similar to the B. subtilis cells treated with 64 µg/mL berberine (Figure S2). These results are also consistent with the reported FtsZ inhibitors, such as benzamide and pyrimidine derivatives,13,29,30 and suggest that CZ74 may disrupt FtsZ function and lead to the abnormal cell division. Figure 2Cell division inhibitory effect of CZ74.…”
Background
The prevalence of drug-resistant bacterial infections urges the development of new antibacterial agents that possess a mechanism of action different from traditional antibiotics. FtsZ has been recognized as a key functional protein in bacterial cell division and it is currently believed to be a potential target for the development of novel antibacterial agents.
Purpose
The primary aim of the study is to screen out an inhibitor targeting at FtsZ and followed to investigate its antibacterial activity and mode of action.
Methods
Cell-based cell division inhibitory screening assay, antimicrobial susceptibility test, minimum bactericidal concentration assay, time-killing curve determination, FtsZ polymerization assay, GTPase activity assay, and molecular modeling were performed in the present study.
Results
The screening study from a small library consisting of benzimidazole and indole derivatives discovered a compound (CZ74) with an indole-core structure. The compound exhibited strong cell division inhibitory effect. In addition, CZ74 shows high antibacterial potency against a number of tested Gram-positive bacteria, such as methicillin-resistant
Staphylococcus aureus
and vancomycin-resistant
Enterococcus
. The minimum inhibitory concentration values obtained were within the range of 2–4 µg/mL. The results of biological study revealed that CZ74 at 2 µg/mL is able to disrupt FtsZ polymerization and inhibit GTPase activity and cell division. From molecular modeling study, CZ74 is found possibly binding into the interdomain cleft of FtsZ protein and then leads to inhibitory effects.
Conclusion
This indole-cored molecule CZ74 could be a potential lead compound and could be further developed as a new generation of antibacterial agents targeting FtsZ to combat against multidrug-resistant bacteria.
“…Recently, Fang and coworkers designed, synthetized, and evaluated novel 2,4-disubtituted-6-thiophenyl-pyrimidines (N5-N8 in Figure 3), which were tested over a number of Gram-positive and Gram-negative bacterial strains (see Table 2), both sensitive and resistant to several antibiotics [14,15]. Their strategy in the design of these molecules was to keep the piperidine ring, which resulted as essential from the previously mentioned STD-NMR studies, and to substitute it with methyl and 4-pyridyl groups at position 2-, to investigate the steric effect at this position.…”
Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome. The constriction of the Z-ring splits the mother bacterial cell into two daughter cells of the same size. The Z-ring is formed by the polymerization of FtsZ, a bacterial protein homologue of eukaryotic tubulin, and it represents the first step of bacterial cytokinesis. The high grade of conservation of FtsZ in most prokaryotic organisms and its relevance in orchestrating the whole division system make this protein a fascinating target in antibiotic research. Indeed, FtsZ inhibition results in the complete blockage of the division system and, consequently, in a bacteriostatic or a bactericidal effect. Since many papers and reviews already discussed the physiology of FtsZ and its auxiliary proteins, as well as the molecular mechanisms in which they are involved, here, we focus on the discussion of the most compelling FtsZ inhibitors, classified by their main protein binding sites and following a medicinal chemistry approach.
“…Pyrimidine compounds and their derivatives have been playing a significant role in the pharmaceutical and pesticide chemistry [3,4]. In recent years, many pyrimidine compounds have displayed applications as antifungal, antibacterial, insecticidal, herbicidal, and antiviral agents [5][6][7][8][9][10]. A series of pyrimidine derivatives have been synthesized, which show novel structure and herbicidal activity [11].…”
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